- Glucocorticoid secretion from the adrenal cortex is stimulated by adrenocorticotropic hormone (ACTH) or corticotropin that is released from the anterior pituitary in response to the hypothalamic-mediated release of corticotropin-releasing hormone (CRH).
- To ensure the proper treatment of Cushing's syndrome, diagnostic procedures should (1) establish the presence of hypercortisolism and (2) discover the underlying etiology of the disease.
- The rationale for treating Cushing's syndrome is to reduce the morbidity and mortality resulting from disorders such as diabetes mellitus, cardiovascular disease, and electrolyte abnormalities.
- The treatment of choice for both ACTH-dependent and ACTH-independent Cushing's syndrome is surgery, whereas pharmacologic agents are reserved for adjunctive therapy, refractory cases, or inoperable disease.
- Pharmacologic agents that may be used to manage the patient with Cushing's syndrome include steroidogenesis inhibitors, adrenolytic agents, neuromodulators of ACTH release, and glucocorticoid-receptor blocking agents.
- Spironolactone, a competitive aldosterone receptor antagonist, is the drug of choice in bilateral adrenal hyperplasia (BAH)-dependent hyperaldosteronism.
- Addison's disease (primary adrenal insufficiency) is a deficiency in cortisol, aldosterone, and various androgens resulting from the loss of function of all regions of the adrenal cortex.
- Secondary adrenal insufficiency usually results from exogenous steroid use, leading to hypothalamic-pituitary-adrenal (HPA)-axis suppression followed by a decrease in ACTH release, and low levels of androgens and cortisol.
- Virilism results from the excessive secretion of androgens from the adrenal gland and often manifests as hirsutism in females.
On completion of the chapter, the reader will be able to:
- 1. Describe the roles of the various zones of the adrenal
cortex in hormone synthesis.
- 2. Explain the regulation of glucocorticoid, adrenal androgen,
and mineralocorticoid secretion.
- 3. Describe and differentiate the various etiologies of Cushing's
- 4. Interpret the results of laboratory tests used to diagnose
- 5. Compare and contrast therapeutic regimens for treatment
of Cushing's syndrome, based on the etiology of the disease in a particular
- 6. Discuss the methods of, and rationale behind, steroid replacement
in the treatment of adrenal adenoma.
- 7. Explain the difference between primary and secondary aldosteronism.
- 8. Interpret the results of laboratory tests used to diagnose
- 9. Recommend a therapeutic regimen for treatment of primary
aldosteronism, based on the etiology of the disease in a particular
- 10. Compare and contrast the symptoms and presentation of
patients with primary and secondary adrenal insufficiency.
- 11. Construct a treatment plan for a patient with acute adrenal
- 12. Describe how specific enzyme deficiencies lead to congenital
- 13. List several options for the treatment of hirsutism.
- 14. Discuss some of the potential side effects of systemic
glucocorticoid use, and how the risk of developing these side effects
can be minimized.
- 15. Recommend appropriate counseling points for a patient
initiating long-term glucocorticoid therapy.
The adrenal glands were first characterized by Eustachius in 1563. After Addison identified a case of adrenal insufficiency in humans, adrenal anatomy and physiology flourished. Most of the work done in the early and mid-1900s centered on the glucocorticoid cortisol. With the discovery of aldosterone by Simpson and Tait in 1952, adrenal pharmacology turned toward the mineralocorticoid. Conn1 followed with his classical description of primary aldosteronism in 1955, and numerous clinicians and investigators have continued to explore the variety of disease processes promoted through the adrenal gland.
The adrenal glands are located extraperitoneally to the upper poles of each kidney (Fig. 85–1). On average, each adrenal gland weighs 4 g and is 2 to 3 cm in width and 4 to 6 cm in length. The gland is fed by small arteries from the abdominal aorta and renal and phrenic arteries. Drainage of the adrenal gland occurs via the renal vein on the left and the inferior vena cava on the right.
Anatomy of the adrenal gland.
The adrenal medulla occupies 10% of the total gland and is responsible for the secretion of catecholamines. The adrenal cortex accounts for the remaining 90% and is responsible for the secretion of three types of hormones (Fig. 85–2) from three separate zones.
Hormone synthetic pathways in relation to the zones of the adrenal cortex.
The zona glomerulosa accounts for 15% of the total adrenal cortex and is responsible for mineralocorticoid production, of which aldosterone is the principal end product. Aldosterone maintains electrolyte and volume homeostasis by altering potassium and magnesium secretion and renal tubular sodium reabsorption. The zona fasciculata, the middle zone, makes up 60% of the cortex, is high in cholesterol, and is responsible for basal and stimulated glucocorticoid production. Glucocorticoids, mainly cortisol, are responsible for the regulation of fat, carbohydrate, and protein metabolism. The zona reticularis occupies 25% of the adrenal cortex, and is responsible for adrenal androgen production. The androgens, testosterone and estradiol, are the major end products and influence the reproductive system in addition to modulating primary and secondary sex characteristics.
Hormone Production and Metabolism
Adrenal steroid hormone synthesis begins with the conversion of cholesterol to pregnenolone by cytochrome P450 (CYP) enzymatic side-chain cleavage. Following this rate-limiting step, pregnenolone is converted to various 19- and 21-carbon steroids, depending on the enzymatic capabilities within each zone of the cortex. Androgenic properties predominate in the 19-carbon steroids, whereas mineralocorticoid and glucocorticoid properties manifest in the 21-carbon steroids.
Aldosterone production is initiated by the 21-hydroxylation of progesterone to form deoxycorticosterone. Subsequently, aldosterone synthase converts deoxycorticosterone to aldosterone through the intermediary, corticosterone. The zona glomerulosa preferentially produces aldosterone for three main reasons. First, the zona glomerulosa lacks 17α-hydroxylase activity and therefore can only convert pregnenolone to progesterone. Secondly, in contrast to the other zones, cells in the zona glomerulosa possess aldosterone synthase activity, which catalyzes the terminal steps ...